1. Field of the Invention
The present invention relates to methods for controlling and/or lowering serum triglyceride and/or cholesterol levels in mammals.
2. Discussion of the Background
Coronary heart disease (CHD) and stroke combine to take by far the greatest toll of life among the more frequent causes of death. Actually, CHD, alone, exceeds other causes of death.
The advent of particularly saluretic antihypertensive therapy has lowered the incidence of stroke impressively, but not the incidence of death from CHD. The fact that commonly prescribed antihypertensive thiazides increase triglyceride blood levels and increase hypercholesterolemia in some patients may contribute to this risk of a greater mortality from CHD when such therapy is employed. Similarly, the nephrology literature recognizes hypertriglyceridemia as a likely risk factor for myocardial infarction in chronic renal failure patients. The Framingham Study has recently affirmed triglycerides as a primary risk factor.
Hypercholesterolemia, particularly increased low density lipoproteinemia-cholesterol (LDL) and hypertriglyceridemia, associated with particularly very low density lipoproteinemia-cholesterol (VLDL), may coexist in the atherosclerotic patient or may exist separately. Likewise, some forms of therapy are better suited to reduction of one or another type of hyperlipidemia. For instance, the bile acid sequestrants, such as cholestyramine and cholestipol decrease LDL cholesterol but are not effective in lowering triglyceridemia. The dosage of 4 or 5 grams taken as a suspension orally twice a day limits their acceptance by the patient. Nicotinic acid is effective and safe for lowering particularly triglyceridemia, but the dosage of 1.5 to 3 grams/day must be worked up to gradually to minimize the flushing and itching of skin which frequently cannot be tolerated by the patient.
Inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase are particularly effective in primary hypercholesterolemia. Of these, lovastatin has recently become the first marketed, so that reduction of CHD incidence by these agents has not been established; nor are these primarily trigylceride-lowering agents. Clofibrate and gemfibrozil are fibric acid derivatives. The latter agent is the newer and may be the safer. It has been reported to be capable of lowering triglyceride and/or LDL cholesterol levels.
In the adult person, hypercholesterolemia usually is attended by hypertension. Whereas a low salt diet may reduce high blood pressure somewhat, it does not reduce hypercholesterolemia. Likewise, a low protein diet employed for reduction of hyperuremia in the patient having chronic progressive renal failure does not reduce hypertriglyceridemia; neither does any form of dialysis treatment.
Coadministration of antihypertensive therapy per se with inhibitors of hypercholesterolemia or hypertriglyceridemia is customary even though the more generally prescribed thiazides or beta-adrenergic blocking agents for hypertension may offset in some measure by their own effects the desired reduction in lipoprotein blood levels, and so are counterproductive with respect to lowering cholesterol and triglyceride blood levels.
Cragoe et al., U.S. Pat. No. 3,313,813, describe 3-amino-5,6-disubstituted-pyrazinoyl guanidines and their use as diuretic, natriuretic agents which selectively enhance the excretion of sodium ions without causing an increase in excretion of potassium ions. Amiloride, a compound of the formula ##STR1## is one of the compounds disclosed in Cragoe et al and the most successfully used compound disclosed in that publication, has been found to possess no advantageous activity towards the control or lowering of serum triglyceride and/or cholesterol levels. A study by Leary et al published in "SA Mediese Tydskrif" (1981), pp. 381-384, reports that the administration of a combination of amiloride and hydrochlorothiazide does not change the plasma cholesterol level in a patient and actually increases the serum triglyceride level.
There is thus a strongly felt need for new methods for the control and/or lowering of serum triglyceride and/or cholesterol levels in mammals, e.g. humans.